[1,2,4]triazolo[4,3-a]quinoxalinone derivatives, their preparation and use

ABSTRACT

The present invention relates to [1,2,4]triazolo[4,3-a]quinoxalinone compounds of the formula ##STR1## wherein R 1  is POX&#39;X&#34; or alkyl substituted with COX&#39; or POX&#39;X&#34;, and X&#39; and X&#34; independently are hydroxy or alkoxy, and R 7  is trifluoromethyl, and R 6 , R 8  and R 9  independently are piperidino, piperazinyl, morpholino, or thiomorpholino, which rings are optionally substituted with one or more of phenyl or C 1-6  -alkyl and phenyl optionally being substituted with C 1-6  -alkoxy; and pharmaceutically acceptable salts thereof. The compounds of the present invention are useful in the treatment of indications caused by hyperactivity of the excitatory neurotransmitters.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 35 U.S.C. 371 national application ofPCT/DK95/00364 filed Mar. 21, 1996 and claims priority under 35 U.S.C.119 of Danish application 1065/94 filed Sep. 16, 1994, the contents ofwhich are fully incorporated by reference.

The present invention relates to therapeutically active heterocycliccompounds, a method of preparing the same, pharmaceutical compositionscomprising the compounds, and a method of treating therewith.

More specifically, the invention relates to[1,2,4]triazolo[4,3-a]quinoxalinone derivatives, which are useful in thetreatment of any indication caused by hyperactivity of excitatory aminoacids.

Various related compounds are known from the prior art.

Thus, EP-A-0040401 generically describes inter aliatriazoloquinoxalin-4-ones substituted at the triazolo ring with e.g. analkyl, acyl or carbalkoxy group. These compounds are claimed to possessuseful anti-hypertensive activity.

In U.S. Pat. No. 5,153,196 some excitatory amino acid receptorantagonists and methods for the use thereof are disclosed. The compoundsconform inter alia to triazoloquinoxalinones having one substituentbeing H, alkyl, aromatic or CF₃ at the triazolo ring.

Further, international patent publication No. WO 93/20077 deals interalia with fused quinoxalinone derivatives optionally substituted in thetriazolo-ring with lower alkyl which may be substituted by mono- ordi(lower alkyl)amino.

L-glutamic acid, L-aspartic acid and a number of other closely relatedamino acids have in common the ability to activate neurons in thecentral nervous system (CNS). Biochemical, electrophysiological andpharmacological studies have substantiated this and demonstrated thatacidic amino acids are transmitters for the vast majority of excitatoryneurons in the mammalian CNS.

Interaction with glutamic acid mediated neurotransmission is considereda useful approach in the treatment of neurological and psychiatricdiseases. Thus, known antagonists of excitatory amino acids have shownpotent anxiolytic (Stephens et al., Psychopharmacology,90, 143-147,1985), anticonvulsant (Croucher et al., Science 216, 899-901, 1982) andmuscle relaxant properties (Turski et al., Neurosci. Lett. 53, 321-326,1985).

It has been suggested that accumulation of extracellular excitatoryamino acids, followed by overstimulation of neurons, may explain theneuronal degenerations seen in neurological disorders such asamyotrophic lateral sclerosis, Parkinsonism, Alzheimer's disease,Huntington's disease, epilepsy, and deficiencies of mental and motorperformance seen after conditions of brain ischemia, anoxia andhypoglycemia or head and spinal cord trauma (McGeer et al., Nature 263,517-519, 1976; Simon et al., Science 226, 850-852, 1984; Wieloch,Science 230, 681-683, 1985; Faden et al., Science 244, 798-800, 1989;Turski et al., Nature 349, 414-418, 1991). Other possible indicationsare psychosis, muscle rigidity, emesis and analgesia.

Excitatory amino acids exert their actions via specific receptorslocated postsynaptically or presynaptically. Such receptors are atpresent conveniently subdivided into three groups bases onelectrophysiological and neurochemical evidence: 1 the NMDA(N-methyl-D-aspartate) receptors, 2 the AMPA receptors, and 3 thekainate receptors. L-glutamic acid and L-aspartic acid probably activateall the above types of excitatory amino acid receptors and possiblyother types as well.

The above mentioned classification of excitatory amino acid receptorsinto NMDA, AMPA, and kainate receptors is based primarily on thefollowing electrophysiological and neurochemical findings.

1) N-methyl-D-aspartate (NMDA) receptors exhibit high selectivity forthe excitant NMDA. Ibotenic acid, L-homocysteic acid, D-glutamic acidand trans-2,3-piperidine dicarboxylic acid (trans-2,3-PDA) exert astrong to moderate agonist activity on these receptors. The most potentand selective antagonists are the D-isomers of the2-amino-5-phosphonocarboxylic acids, e.g. 2-amino-5-phosphono-valericacid (D-APV) and 3-[(±)-2-carboxy-piperazin-4-yl]-propyl-1-phosphonicacid (CPP), while moderate antagonist activity is shown by the D-isomersof long chain 2-amino dicarboxylic acids (e.g. D-2-amino-adipic acid)and long chain diaminodicarboxylic acids (e.g. diaminopimelic acid). TheNMDA-induced synaptical responses have been extensively investigated inthe mammalian CNS, especially in the spinal cord (J. Davies et al., J.Physiol. 297, 621-635, 1979) and the responses have been shown to bestrongly inhibited by Mg²⁺.

2) AMPA receptors are activated selectively by AMPA(2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), other potentagonists being quisqualic acid and L-glutamic acid. Glutamic aciddiethyl ester (GDEE) is a selective but very weak antagonist of thissite. AMPA receptors are relatively insensitive to Mg²⁺.

Glutamate release has long been thought to play a major role in neuronaldeath resulting from cerebral ischemia (Benveniste, H. et al., J.Neurochem. 43, 1369-1374, 1984). It is well known that NMDA receptorevoked Ca²⁺ influx is an important mechanism in ischemic neuronal cellloss. The non-NMDA receptor coupled ionophor is not permeable tocalcium. However, the excitation by the Scaffer collaterals in the CA1region is excerted by non-NMDA receptors, and this fact is of importancefor the events in the postischemic period. Recent studies have shownthat selective AMPA antagonists have neuroprotectant effects in globalischemia in the gerbil even when given several hours after reperfusion(Sheardown et al., Science 247, 571-574, 1990).

AMPA antagonists are therefore useful in the treatment of cerebralischemia.

3) Kainate receptors. Excitatory responses to kainic acid are relativelyinsensitive to antagonism by NMDA-antagonists and by GDEE, and it hasbeen proposed that kainic acid activates a third subclass of acidicamino acid receptor. Certain lactonized derivatives of kainic acid areselective antagonists (O. Goldberg et al., Neurosci. Lett. 23, 187-191,1981) and the dipeptide 3-glutamyl-glycine also shows some selectivityfor kainate receptors. Ca²⁺ but not Mg²⁺ is a strong inhibitor of kainicacid binding.

The affinity of a substance for one or more of the different types ofexcitatory amino acid receptors may be studied in simple bindingexperiments. In essence, the method involves incubation of a particularselected radiolabelled ligand and the particular specific substance tobe investigated with brain homogenate which contains the receptor.Measurement of receptor occupancy is made by determination of theradioactivity bound to the homogenate and subtraction of nonspecificbinding.

AMPA receptor binding may be studied by using ³ H-AMPA as radioligand.

The influence of glutamic acid analogues on secondary effects ofglutamate receptor interactions may be studied in vitro by using thephenomenon of spreading depression in chicken retina. Such experimentswill provide information as to the efficacies (agonist/antagonist) ofthe test substances. This is in contrast to binding studies, which onlyprovide information on the affinities of the compounds for the receptor.

It has now been found that the compounds of the invention have affinityfor the AMPA receptors and are antagonists in connection with this typeof receptor which makes them useful in the treatment of any of thenumerous indications caused by hyperactivity of excitatory amino acids,especially neuronal degeneration as are observed in amyotrophic lateralsclerosis, Huntington's chorea, Parkinson's disease, epilepsy and seniledementia or mental and motor dysfunctions seen after conditions of brainischemia, oxygen deficiency, hypoglycemia and head and spinal cordtrauma. Other possible indications are psychosis, muscle rigidity,emesis, acute and chronic inflammatory disease and analgesia.

The compounds of the invention are represented by the general formula I##STR2## wherein R¹ is POX'X" or straight or branched C₁₋₆ -alkylsubstituted with COX' or POX'X" and X' and X" independently are hydroxyor C₁₋₆ -alkoxy, and

R⁶, R⁷, R⁸ and R⁹ independently are hydrogen; C₁₋₆ -alkyl; halogen; NH₂; NO₂ ; CN; CF₃ ; SO₂ NY'Y"; COZ' wherein Z' is NY'Y" or C₁₋₆ -alkyl,and Y' and Y" independently are hydrogen or C₁₋₆ -alkyl; triazolyl;imidazolyl; piperidino; piperazinyl; morpholino; thiomorpholino, whichrings are optionally substituted with one or more of phenyl or C₁₋₆-alkyl and phenyl optionally being substituted with C₁₋₆ -alkoxy; andpharmaceutically acceptable salts thereof.

The term "C₁₋₆ -alkyl" as used herein refers to a straight or branched,saturated hydrocarbon chain having 1-6 carbon atoms such as methyl,ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, tert.butyl, 3-pentyl,neopentyl or n-hexyl.

The term "C₁₋₆ -alkoxy" as used herein, alone or in combination, refersto a monovalent substituent comprising a C₁₋₆ -alkyl group linkedthrough an ether oxygen having its free valence bond from the etheroxygen, e.g. methoxy, ethoxy, propoxy, isopropoxy, cyclopropylmethoxy,butoxy, pentoxy.

The term "halogen" as used herein means fluorine, chlorine, bromine andiodine.

In a preferred embodiment of the invention R¹ is C₁₋₆ -alkyl substitutedwith COX' or POX'X".

In another preferred embodiment of the invention R⁶, R⁷, R⁸ and R⁹ areindependently hydrogen; chlorine; NO₂ ; CN; CF₃ ; piperidino;morpholino; thiomorpholino; piperazinyl; piperazinyl substituted withmethyl, phenyl or methoxyphenyl; triazolyl disubstituted with methyl;imidazolyl disubstituted with methyl, ethyl, phenyl.

In yet another preferred embodiment of the invention R⁶ and R⁹ arehydrogen.

Preferred compounds of the invention are:

1-(Ethoxy-hydroxy-phosphorylmethyl)-8-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

8-(4-Methyl-2-phenyl-1H-imidazol-1-yl)-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

1-(Ethoxy-hydroxy-phosphorylmethyl)-8-(2-ethyl-4-methyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

8-(2-Ethyl-4-methyl-1H-imidazol-1-yl)-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

8-Morpholino-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

8-Morpholino-1-(1-phosphonoethyl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

8-Piperidino-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

1-(2-Ethoxycarbonylethyl)-8-morpholino-7-trifluoromethyl[1,2,4]triazolo-[4,3-a]quinoxalin-4(5H)-one;

1-(2-Carboxyethyl)-8-morpholino-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one.

Other preferred compounds of the invention are:

8-(2,4-Dimethyl-1H-imidazol-1-yl)-1-phosphonomethyl-7-trifluoromethyl-[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

7-Cyano-8-(2,4-dimethyl-1H-imidazol-1-yl)-1-phosphonomethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

8-(2,4-Dimethyl-1H-imidazol-1-yl)-7-nitro-1-phosphonomethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

7-Cyano-8-(2-ethyl-4-methyl-1H-imidazol-1-yl)-1-phosphonomethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

7-Cyano-8-morpholino-1-phosphonomethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

8-Morpholino-7-nitro-1-phosphonomethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

7-Cyano-1-phosphonomethyl-8-thiomorpholino[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

1-Phosphonomethyl-8-thiomorpholino-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

7-Cyano-1-phosphonomethyl-8-piperidino[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

1-Phosphonomethyl-8-(piperazin-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

7-Cyano-1-phosphonomethyl-8-(piperazin-1-yl)[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

8-(4-Phenylpiperazin-1-yl)-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

7-Cyano-8-(4-phenylpiperazin-1-yl)-1-phosphonomethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

8-(4-(3-Methoxyphenyl)piperazin-1-yl)-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

8-(4-(4-Methoxyphenyl)piperazin-1-yl)-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

8-(2,4-Dimethyl-1H-imidazol-1-yl)-1-phosphonoethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

7-Chloro-8-(2,4-dimethyl-1H-imidazol-1-yl)-1-phosphonomethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

8-(3,5-Dimethyl-1,2,4-triazol-1-yl)-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

8-(4-Methylpiperazin-1-yl)-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

1-(2-Carboxyethyl)-8-(2,4-dimethyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

1-(2-Carboxyethyl)-8-(2-ethyl-4-methyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

1-(2-Carboxyethyl)-7-cyano-8-(2,4-dimethyl-1H-imidazol-1-yl)[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

1-(2-Carboxyethyl)-8-(4-phenylpiperazin-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

1-(2-Carboxyethyl)-8-(2,4-dimethyl-1H-imidazol-1-yl)-7-nitro[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

1-(2-Carboxyethyl)-7-cyano-8-morpholino[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

1-(2-Carboxyethyl)-8-morpholino-7-nitro[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

1-(2-Carboxyethyl)-8-(4-methylpiperazin-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

1-(2-Carboxyethyl)-7-chloro-8-(2,4-dimethyl-1H-imidazol-1-yl)[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

1-(2-Carboxyethyl)-8-(4-(4-methoxyphenyl)piperazin-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;

1-(2-Carboxyethyl)-8-piperidino-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one.

The compounds of the invention may be present in different tautomericforms. Therefore the invention includes all such tautomeric forms.

Another embodiment of the invention is pharmaceutically acceptable saltsof [1,2,4]triazolo[4,3-a]quinoxalinone derivatives of formula I. Suchsalts include those derived from inorganic and organic acids such ashydrochloric acid, hydrobromic acid, acetic acid, sulfuric acid, nitricacid, oxalic acid, fumaric acid, tartaric acid, etc. Other salts includealkali metal salts such as sodium or potassium salts; alkaline earthmetal salts such as calcium or magnesium salts; and ammonium salts.

Further, in another aspect the invention relates to a compound of thegeneral formula (I) or a pharmaceutically acceptable salt thereof foruse as a medicament, preferably for use as a medicament for treating anindication related to hyperactivity of exitatory neurotransmitters andparticularly the AMPA receptors.

The invention also relates to a method of preparing the above mentionedcompounds. The present compounds of formula I are prepared by

a) alkylating a compound having the formula II ##STR3## wherein R⁶, R⁷,R⁸ and R⁹ have the meanings defined above with benzylhalogenide to forma compound of the formula III ##STR4## wherein R⁶, R⁷, R⁸ and R⁹ havethe meanings defined above, and halogenating the compound to form acompound of the formula IV ##STR5## wherein R⁶, R⁷, R⁸ and R⁹ have themeanings defined above and Q is Br, Cl, or I; and reacting the compoundwith hydrazine to form a compound of the formula V ##STR6## wherein R⁶,R⁷, R⁸ and R⁹ have the meanings defined above, and acylating thecompound with an acylchloride with the general formula VI

    R.sup.1 --COCl                                             (VI)

wherein R¹ has the meaning as defined above for a compound of thegeneral formula I wherein X' and X" are C₁₋₆ -alkoxy to form a compoundof the formula VII ##STR7## wherein R¹, R⁶, R⁷, R⁸ and R⁹ have themeanings defined above, and hydrogenolysis of the compound to form acompound of the formula VIII ##STR8## wherein R¹, R⁶, R⁷, R⁸ and R⁹ havethe meanings defined above, and followed by thermal cyclization andsimultaneous deoxygenation to form a compound of formula I, wherein X'and X" independently are hydroxy or C₁₋₆ -alkoxy, or

b) reacting a compound having the formula IX ##STR9## wherein R⁶, R⁷, R⁸and R⁹ have the meanings defined above, and Q is Br, Cl or I, with acompound of the general formula VI

    R.sup.1 --COCl                                             (VI)

wherein R¹ has the meaning as defined above for a compound of thegeneral formula I wherein X' and X" are C₁₋₆ -alkoxy to form a compoundof the formula XI ##STR10## wherein R¹, R⁶, R⁷, R⁸ and R⁹ have themeanings defined above, and Q is Br, Cl or I, and then eithercyclization followed by hydrolysis or simultaneous cyclization andhydrolysis to form a compound of formula I, wherein X' and X"independently are hydroxy or C₁₋₆ -alkoxy, or

c) substituting a compound of the formula XII ##STR11## wherein R⁶, R⁷,R⁸ and R⁹ have the meanings defined above and Z is either halogen orC₁₋₆ -alkoxy with mono-, di-, or trimethoxy substituted benzylamine toform a compound of formula XIII ##STR12## wherein R⁶, R⁷, R⁸ and R⁹ havethe meanings defined above, and V' and V" independently are hydrogen ormethoxy, and reacting the compound with ethyloxalylchloride to form acompound of formula XIV ##STR13## wherein R⁶, R⁷, R⁸ and R⁹ have themeanings defined above, and V' and V" independently are hydrogen ormethoxy, and then either hydrogenation to form the intermediate cyclizedN-hydroxy compound followed by deoxygenation or cyclization byhydrogenation to form a compound of formula XV ##STR14## wherein R⁶, R⁷,R⁸ and R⁹ have the meanings defined above, and V' and V" independentlyare hydrogen or methoxy, halogenating the compound of formula XV,reacting the resulting compound with hydrazine followed by acylatingwith an acylchloride of the general formula VI as defined above, andthen cyclization to form a compound of formula XVI ##STR15## wherein R¹,R⁶, R⁷, R⁸ and R⁹ have the meanings defined above, and V' and V"independently are hydrogen or methoxy, and hydrolysis to form a compoundof formula I, wherein X' and X" independently are hydrogen or C₁₋₆-alkoxy, or

d) hydrolysing a compound of formula I, wherein X' and X" are C₁₋₆-alkoxy with aqueous base to form a compound of formula I, wherein X' ishydroxy, and X" is C₁₋₆ -alkoxy, or

e) reacting a compound of formula I, wherein X' is hydroxy or C₁₋₆-alkoxy, and X" is C₁₋₆ -alkoxy with halotrimethylsilane to form acompound of formula I, wherein X' and X" are hydroxy.

Pharmaceutically acceptable salts may be prepared according to standardprocedures by treating a compound of formula I with the appropriateacids or bases.

The starting materials for which the preparation is not described hereinare either known compounds (e.g. from International appl. no.PCT-DK94/00170) or compounds which may be prepared in analogy with thepreparation of known compounds or in analogy with known methods.

The pharmacological properties of the compounds of the present inventioncan be illustrated by determining their capability for displacingradioactively labelled 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid (AMPA) from the AMPA type receptors. The antagonistic properties ofthe compounds is demonstrated by their capability to antagonizequisqualic acid stimulated spreading depression in chicken retina.

The displacement activity of the compounds may be shown by determiningthe IC₅₀ value which represents the concentration (μM) which causes adisplacement of 50% of the specific binding of ³ H-AMPA.

The antagonism is measured by determining the IC₅₀ value whichrepresents the concentration which produces a 50% maximal inhibition ofquisqualic acid stimulated spreading depression in chicken retina.

³ H-AMPA Binding (Test 1)

500 μl of thawed rat cerebral cortical membrane homogenate in Tris-HCl(30 mM), CaCl₂ (2.5 mM) and KSCN (100 mM) pH 7.1 were incubated at 0° C.for 30 min. with 25 μl ³ H-AMPA (5 nM final concentration) and the testcompound and buffer. Nonspecific binding was determined by incubationwith L-glutamic acid (600 μM final concentration). The binding reactionwas terminated by adding 5 ml of ice-cold buffer followed by filtrationthrough Whatman GF/C glass fibre filters and 2×5 ml wash with ice-coldbuffer. Bound radioactivity was measured by scintillation counting. IC₅₀was determined by Hill analysis of at least four concentrations of testcompound.

Spreading Depression (Test 2)

Chicks (3-10 days old) were decapitated, the eyes enucleated andsectioned along the equatorial plane. After removal of the anteriorchamber and the vitreous body, the posterior chamber of each eye wasplaced in a small petri dish containing a physiological saline solution(P.S.S.) of the following composition (mM) NaCl (100), KCl (6.0), CaCl₂(1.0), MgSO₄ (1.0), NaHCO₃ (30), NaH₂ PO₄ (1.0), glucose (20).

The solution was saturated with 100% O₂ and maintained at a temperatureof 26° C.

The eyes were initially incubated in normal P.S.S. for 15-30 min. andthen transferred to P.S.S. containing quisqualate (1 μg/ml). In this"stimulating solution" S.D.s start spontaneously usually from the edgeof the retina, and can be easily observed by eye. The time taken for anS.D. to start in each eye was measured.

After a further 15 min. of incubation in normal P.S.S. the eyes weretransferred to normal P.S.S. containing the test compound and incubatedfor 15 min. Thereafter the eyes were transferred to a "stimulatingsolution" containing the same concentration of the test compound. Thetime taken for an S.D. to start in each eye was measured again. The eyeswere then placed back in normal P.S.S. and after 15 min. the time takenfor S.D. to start was measured again, in order to assess the degree ofrecovery from any drug effects.

An increase in the time taken for S.D. to start of 30 seconds more thanthe control time is considered 100% inhibition of S.D. The drug effectstherefore are expressed as the percentage maximum response obtained fora given dose. The test value can be quoted therefore as theconcentration (μM) of test substance which produces a 50% maximalinhibition (IC₅₀).

Test results obtained by testing some compounds of the present inventionare shown in the following table 1.

                  TABLE 1                                                         ______________________________________                                                         TEST 1  TEST 2                                                 Compound of IC.sub.50 IC.sub.50                                               example μM μM                                                         ______________________________________                                        2                0.39    0.40                                                 ______________________________________                                    

The pharmaceutical preparations of compositions comprising the compoundsof the invention may be administered to humans or animals by oral,rectal or parenteral route.

An effective amount of the active compound or a pharmaceuticallyacceptable salt thereof may be determined in accordance with the usualfactors, such as the nature and severity of the condition and the weightof the mammal requiring treatment.

Conventional excipients are such pharmaceutically acceptable organic orinorganic carrier substances suitable for parenteral or enteralapplication which do not deleteriously react with the active compounds.

Examples of such carriers are water, salt solutions, alcohols,polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine,lactose, amylose, magnesium stearate, talc, silicic acid, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired,with auxiliary agents, such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salt for influencing osmotic pressure,buffers and/or colouring substances and the like, which do notdeleteriously react with the active compounds.

Injectable solutions or suspensions, preferably aqueous solutions withthe active compound dissolved in polyhydroxylated castor oil, areparticularly suitable for parenteral administration.

Ampoules are convenient unit dosage forms.

Tablets, dragees, or capsules containing talc and/or a carrier or binderor the like are particularly suitable for oral administration. Thecarrier preferably is lactose and/or corn starch and/or potato starch.

A syrup, elixir, or the like can be used in the cases where a sweetenedvehicle can be employed or is desired.

Generally, the compounds of this invention are dispensed in unit dosageform comprising 0.5-1000 mg of active ingredient in or together with apharmaceutically acceptable carrier per unit dosage.

The dosage of the compounds according to this invention is 1-500 mg/day,e.g. about 50-100 mg per dose, when administered to patients, e.g.humans, as a drug.

A typical tablet which may be prepared by conventional tablettingtechniques contains:

    ______________________________________                                        Core:                                                                           Active compound (as free compound 100 mg                                      or salt thereof)                                                              Colloidal silicon dioxide (Aerosil                                                                            ®) 1.5 mg                                 Cellulose, microcryst. (Avicel ®) 70 mg                                   Modified cellulose gum (Ac-Di-Sol ®) 7.5 mg                               Magnesium stearate 1 mg                                                       Coating:                                                                      HPMC approx. 9 mg                                                             *Mywacett ® 9-40T approx. 0.9 mg                                        ______________________________________                                         *Acylated monoglyceride used as plasticizer for filmcoating              

The free compounds of the present invention which form alkali metal oralkaline earth metal salts may be employed in such salt form. Suchalkali metal or earth alkali metal salts are ordinarily formed byreacting the compound with an equivalent amount or excess of theselected alkali metal or earth alkali metal as the hydroxide, frequentlyand suitably by admixture in the presence of a neutral solvent, fromwhich the salt may be precipitated or recovered in other conventionalmanner, e.g. by evaporation. Administration of a compound of theinvention is often preferably in the form of a pharmaceuticallyacceptable water-soluble alkali metal or earth alkali metal saltthereof, and orally, rectally, or parenterally in the form of apharmaceutical composition wherein it is present together with apharmaceutically acceptable liquid or solid carrier or diluent.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may be placed into the form of pharmaceuticalcompositions and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids, such assolutions, suspensions, emulsions, elixirs, or capsules filled with thesame, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceutical compositionand unit dosage forms thereof may comprise conventional ingredients inconventional proportions, with or without additional active compounds orprinciples, and such unit dosage forms may contain any suitableeffective AMPA antagonistic amount of the active ingredient commensuratewith the intended daily dosage range to be employed. Tablets containing1-500 mg of active ingredient or, more specified 10-200 mg, per tablet,are accordingly suitable representative unit dosage forms.

Due to their high degree of AMPA antagonistic activity and their lowtoxicity, together presenting a most favourable therapeutic index, thecompounds of the invention may be administered to a subject, e.g. aliving animal body, in need of such treatment, elimination, alleviation,or amelioration of an indication which is sensitive to a change in theAMPA receptor condition, e.g. sclerosis, Parkinsonism, Alzheimer'sdisease, Huntington's disease, epilepsy, deficiencies seen afterischemia, anoxia, hypoglycemia, head and spinal cord trauma, psychosis,muscle rigidity, emesis and analgesia, often preferably in the form ofan alkali metal or earth alkali metal salt thereof, concurrently,simultaneously, or together with a pharmaceutically acceptable carrieror diluent, especially and preferably in the form of a pharmaceuticalcomposition thereof, whether by oral, rectal, or parenteral (includingsubcutaneous) route, in an effective amount.

Suitable dosage ranges are 1-500 mg daily, preferably 10-200 mg daily,and especially 50-100 mg daily, depending as usual upon the exact modeof administration, form in which administered, the indication towardswhich the administration is directed, the subject involved and the bodyweight of the subject involved, and the preference and experience of thephysician or veterinarian in charge.

Such method of treating may be described as the treatment of anindication caused by or related to hyperactivity of the excitatoryneurotransmitters, and particularly the AMPA receptors in a subject inneed thereof, which comprises the step of administering to the saidsubject a neurologically effective amount of an AMPA antagonisticcompound of the invention, or a pharmaceutically acceptable saltthereof.

Furthermore, the present invention relates to the use of a compound ofthe invention for preparing a medicament for treating an indicationcaused by or related to hyperactivity of the excitatoryneurotransmitters, and particularly the AMPA receptors in a subject inneed thereof.

The invention will now be described in further detail with reference tothe following examples:

EXAMPLE 11-(Ethoxy-hydroxy-phosphorylmethyl)-8-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one

a.1-Benzyloxy-3-chloro-6-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one,hydrochloride

A solution of 20% phosgene in toluene (18.2 ml, 35 mmol) was addeddropwise to a stirred solution of1-benzyloxy-6-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxaline-2,3(1H,4H)-dione(8.8 g, 17.5 mmol) in 100 ml of dry N,N-dimethylformamide at 0° C. Themixture was stirred at room temperature overnight and the precipitatedsolid was isolated by filtration and washed with ether to give 8.0 g(84%) of the title compound.

¹ H-NMR (DMSO-d₆): δ 6 2.42 (s, 3H), 5.35 (s, 2H), 7.30-7.61 (m, 10H),7.62 (s, 1H), 7.75 (s, 1H), 8.48 (s, 1H).

b.1-Benzyloxy-3-hydrazino-6-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one

A mixture of1-benzyl-3-chloro-6-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-onehydrochloride (2.0 g, 3.6 mmol) and hydrazine hydrate (0.74 ml, 15 mmol)in 40 ml of dichloromethane was stirred at 0° C. for 1 h and evaporatedto dryness in vacuo. The residue was triturated with water to give 1.59g (87%) of the title compound. M.p. 127-130° C.

¹ H-NMR (DMSO-d₆): δ 2.21 (s, 1H), 5.34 (s, 2H), 7.01 (s, 1H), 7.18 (s,1H), 7.27 (s, 5H), 7.37-7.45 (m, 3H), 7.48 (s, 1H), 7.51-7.60 (m, 2H).

c.1-Benzyloxy-3-[2-[(diethoxyphosphoryl)acetyl]hydrazino]-6-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one

A solution of (diethoxyphosphoryl)acetyl chloride (0.67 g, 3.1 mmol) in20 ml of dry tetrahydrofuran was added dropwise to a stirred solution of1-benzyloxy-3-hydrazino-6-(4-methyl-2-phenyl-1H-imidazol-1-(-yl)-7-trifluoromethylquinoxalin-2(1H)-one(1.52 g, 3.0 mmol) and dry triethylamine (0.43 ml, 3.1 mmol) in 50 ml ofdry tetrahydrofuran.

The mixture was stirred overnight at room temperature and thenevaporated to dryness in vacuo. The residue was triturated with watergiving 1.8 g (88%) of the title compound. M.p.>90° C. decomp.

¹ H-NMR (DMSO-d₆): δ 1.10-1.21 (m, 6H), 2.20 (s, 3H), 2.99 (d, 2H), 4.01(quint., 4H), 5.40 (s, 2H), 7.04 (s, 1H), 7.24 (s, 6H), 7.37-7.46 (m,3H), 7.50-7.62 (m, 3H), 10.26 (s, 1H), 10.38 (s, 1H).

d.3-[2-[(Diethoxyphosphoryl)acetyl]hydrazino]-1-hydroxy-6-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one

A suspension of1-benzyloxy-3-[2-[(diethoxyphosphoryl)acetyl]hydrazino]-6-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one(1.8 g, 2.6 mmol) and 50 mg of 5% palladium on carbon in 50 ml ofethanol was hydrogenated at room temperature and atmospheric pressurefor 9 h. The catalyst was removed by filtration, the filtrate evaporatedto dryness in vacuo and the residue finally triturated with ether togive 1.51 g (97%) of the title compound. M.p.>177° C. decomp. ¹ H-NMR(DMSO-d₆): δ 1.10-1.22 (m, 6H), 2.23 (s, 3H), 2.98 (d, 2H), 4.00(quint., 4H), 7.12 (s, 1H), 7.18-7.30 (m, 5H), 7.31 (s, 1H), 7.92 (s,1H), 10.24 (s, 2H), 12.52 (br. s, 1H).

e.1-(Ethoxy-hydroxy-phosphorylmethyl)-8-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one

A solution of3-[2-[(diethoxyphosphoryl)acetyl]hydrazino]-1-hydroxy-6-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one(1.5 g, 2.5 mmol) and triphenylphosphine (1.3 g, 5 mmol) in 50 ml ofglacial acetic acid was stirred overnight at 120° C.

The cooled mixture was filtered and the isolated product was washed withether to give 0.64 g (48%) of the title compound. M.p. 303-308° C.

¹ H-NMR (DMSO-d₆): δ 1.10 (t, 3H), 2.25 (s, 3H), 3.87 (quint., 2H), 3.97(d, 2H), 7.12 (s, 1H), 7.14-7.45 (m, 5H), 7.72 (s, 1H), 8.62 (s, 1H),12.4 (s, 1H).

EXAMPLE 28-(4-Methyl-2-phenyl-1H-imidazol-1-yl)-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one

Bromotrimethylsilane (1 ml, 7 mmol) was added dropwise to a stirredsolution of1-(ethoxy-hydroxy-phosphorylmethyl)-8-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one(500 mg, 0.94 mmol) in 20 ml of dry N,N-dimethylformamide.

The solution was stirred at room temperature overnight and evaporated todryness in vacuo. The residue was triturated with 10 ml of water and theprecipitated solid was isolated by filtration. Washing with a smallamount of water and ethanol gave 0.45 g (95%) of the pure titlecompound. M.p. 321-325° C.

¹ H-NMR (DMSO-d₆): δ 2.35 (s, 3H), 3.93 (d, 2H), 7.22-7.52 (m, 6H), 7.74(s, 1H), 8.79 (s, 1H), 12.4 (s, 1H).

EXAMPLE 31-(Ethoxy-hydroxy-phosphorylmethyl)-8-(2-ethyl-4-methyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one

The title compound was prepared from1-benzyloxy-6-(2-ethyl-4-methyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxaline-2,3(1H,4H)-dioneby a method analogous to the method described in example 1, except thatthe final product (theoretically 10.8 mmol) was worked up in thefollowing way. To the cooled solution was added 100 ml ofdichloromethane and 100 ml of ether. The precipitated solid was isolatedby filtration and extracted with boiling water (2×100 ml). The aqueousphase was concentrated to about 100 ml and cooled on an ice-bath. Theresulting precipitate was isolated by filtration and dried to give 0.90g (17%) of the title compound.

¹ H-NMR (CF₃ COOD): δ 1.38 (t, 3H), 1.45 (t, 3H), 2.51 (s, 3H),2.72-3.10 (m, 2H), 4.31 (quint., 2H), 4.58 (dd, 2H (partiallyexchanged)), 7.22 (s, 1H), 8.32 (s, 1H), 9.00 (s, 1H).

EXAMPLE 48-(2-Ethyl-4-methyl-1H-imidazol-1-yl)-1-phosphonomethyl-7-trifluoromethyl[1,2,4)triazolo[4,3-a]quinoxalin-4(5H)-one

The title compound was prepared from1-(ethoxy-hydroxy-phosphorylmethyl)-8-(2-ethyl-4-methyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one(870 mg, 1.8 mmol) by a method analogous to the method described inexample 2. Yield: 710 mg (86%). M.p.>300° C.

¹ H-NMR (DMSO-d₆): δ 1.10 (t, 3H), 2.20 (s, 3H), 2.27-2.77 (m, 2H),3.62-3.95 (m, 2H), 7.07 (s, 1H), 7.85 (s, 1H), 8.55 (s, 1H); MS (FAB):m/e 457 (MH⁺). (C₁₇ H₁₆ N₆ F₃ O₄ P.1/2H₂ O)

    ______________________________________                                        Calc.:   C 43.88       H 3.68  N 18.06                                          Found: C 44.07 H 3.56 N 18.02                                               ______________________________________                                    

EXAMPLE 58-Morpholino-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one

a.1-(Ethoxy-hydroxy-phosphorylmethyl)-8-morpholino-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one

The title compound was prepared from1-benzyloxy-6-morpholino-7-trifluoromethylquinoxaline-2,3(1H,4H)-dioneby a method analogous to the method described in example 1, except thatthe final product was isolated in the following way. The mixture wasevaporated to dryness in vacuo and the residue was taken up in a mixtureof 200 ml of dichloromethane and 50 ml of chloroform. The resultingsolution was extracted with water (6×100 ml) and the aqueous solutionwas evaporated to dryness under reduced pressure by azeotropicdistillation with 1-propanol to give the crude product, which was usedwithout further purification in the following step.

b.8-Morpholino-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one

The title compound was prepared from crude1-(ethoxy-hydroxy-phosphorylmethyl)-8-morpholino-7-trifluoromethyl[12,4]triazolo[4,3-a]quinoxalin-4(5H)-one by a method analogous to themethod described in example 2. M.p.>300° C decomp. (ethanol).

¹ H-NMR (DMSO-d₆): δ 2.9-3.03 (m, 4H), 3.66-3.78 (m, 4H), 3.98 (d, 2H),7.68 (s, 1H), 8.39 (s, 1H), 12.18 (s, 1H).

EXAMPLE 68-Morpholino-1-(1-phosphonoethyl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one

a.1-(1-(Ethoxy-hydroxy-phosphorylmethyl)-8-morpholino-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one

The title compound was prepared from1-benzyloxy-6-morpholino-7-trifluoromethylquinoxaline-2,3(1H,4H)-dioneby a method analogous to the method described in example 5, except that2-(diethoxyphosphoryl)propionyl chloride was used instead of(diethoxyphosphoryl)acetyl chloride. The crude product was used withoutfurther purification in the following step.

b.8-Morpholino-1-(1-phosphonoethyl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one

The title compound was prepared from crude1-(1-(ethoxy-hydroxy-phosphorylmethyl)-8-morpholino-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-oneby a method analogous to the method described in example 2, except thatthe final product was purified by column chromatography. M.p.>300° C.decomp.

¹ H-NMR (DMSO-d₆): δ 1.73 (dd, 3H), 2.87-3.02 (m, 4H), 3.68-3.78 (m,4H), 4.11-4.38 (m, 1H), 7.68 (s, 1H), 8.38 (s, 1H), 12.18 (s, 1H).

EXAMPLE 78-Piperidino-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one

a.1-(Ethoxy-hydroxy-phosphorylmethyl)-8-piperidino-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one

The title compound was prepared from1-benzyloxy-6-piperidino-7-trifluoromethylquinoxaline-2,3(1H,4H)-dioneby a method analogous to the method described in example 3, except thatthe crude product was used without further purification in the followingstep.

b.8-Piperidino-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one

The title compound was prepared from crude1-(ethoxy-hydroxy-phosphorylmethyl)-8-piperidino-7-trifluoromethyl[1,2,4]triazolo(4,3-a]quinoxalin-4(5H)-oneby a method analogous to the method described in example 2. ¹ H-NMR(DMSO-d₆): δ 1.48-1.72 (m, 6H), 2.83-2.98 (m, 4H), 3.90 (d, 2H), 7.65(s, 1H), 8.32 (s, 1H), 12.12 (s, 1H).

EXAMPLE 81-(2-Ethoxycarbonylethyl)-8-morpholino-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one

The title compound was prepared from1-benzyloxy-6-morpholino-7-trifluoromethylquinoxaline-2,3(1H,4H)-dioneand ethyl succinylchloride by a method analogous to the method describedin example 1, except that the final product was worked up in thefollowing way. The cooled mixture was evaporated to dryness in vacuo andpurified by flash-chromatography successively with dichloromethane andethyl acetate. Trituration with ether afforded the pure product. M.p.204-210° C.

¹ H-NMR (DMSO-d₆): δ 1.22 (t, 3H), 2.88-3.00 (m, 4H), 3.02 (t, 2H),3.61-3.82 (m, 6H), 4.12 (q, 2H), 7.71 (s, 1H), 7.99 (s, 1H), 12.2 (br.s, 1H).

EXAMPLE 91-(2-Carboxyethyl)-8-morpholino-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one

A suspension of1-(2-ethoxycarbonylethyl)-8-morpholino-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one(365 mg, 0.83 mmol) in 10 ml of 2N potassium hydroxide was stirred atroom temperature for 3 h.

The resulting solution was filtered and the filtrate was acidified with4M hydrochloric acid to give a precipitate. The product was isolated byfiltration, washed with water and dried to give the title compound. M.p.170-176° C. ¹ H-NMR (DMSO-d₆): δ 6 2.88-3.02 (m, 6H), 3.67 (t, 2H),3.68-3.80 (m, 4H), 7.71 (s, 1H), 7.99 (s, 1H), 12.26 (br. s, 1H).

What is claimed is:
 1. [1,2,4]Triazolo[4,3-a]quinoxalinone compounds ofthe formula I ##STR16## wherein R¹ is POX'X" or straight or branchedC₁₋₆ -alkyl substituted with COX' or POX'X", and X' and X" independentlyare hydroxy or C₁₋₆ -alkoxy, andR⁶, R⁸ and R⁹ independently arepiperidino; piperazinyl; morpholino; or thiomorpholino, which rings areoptionally substituted with one or more of phenyl or C₁₋₆ -alkyl andphenyl optionally being substituted with C₁₋₆ -alkoxy; or R⁶ and R⁹independently are hydrogen; and R⁷ is trifluoromethyl; andpharmaceutically acceptable salts thereof.
 2. A compound according toclaim 1 wherein R¹ is C₁₋₆ -alkyl substituted with COX' or POX'X".
 3. Acompound according to claim 1 wherein R⁶, R⁸ and R⁹ independently arepiperidino; morpholino; thiomorpholino; piperazinyl; or piperazinylsubstituted with methyl, phenyl or methoxyphenyl.
 4. A compoundaccording to claim 1 whichis8-Morpholino-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;8-Morpholino-1-(1-phosphonoethyl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;8-Piperidino-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;1-(2-Ethoxycarbonylethyl)-8-morpholino-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one;or1-(2-Carboxyethyl)-8-morpholino-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one.5. A pharmaceutical composition comprising as active component acompound according to claim 1 or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier or diluent.
 6. Apharmaceutical composition according to claim 5 in the form of a dosageunit containing about 10-200 mg of the active compound.
 7. A method oftreating neuronal degeneration comprising administering to a subject inneed thereof a neurologically effective AMPA antagonistic amount of acompound according to claim 1 or a pharmaceutically acceptable saltthereof.
 8. A method according to claim 7, wherein the indication isrelated to cerebral ischemia.
 9. A method of preparing the compounds offormula I according to claim 1, which comprisesa) alkylating a compoundhaving the formula II ##STR17## wherein R⁶, R⁷, R⁸ and R⁹ have themeanings defined above with benzylhalogenide to form a compound of theformula III ##STR18## wherein R⁶, R⁷, R⁸ and R⁹ have the meaningsdefined above, and halogenating the compound to form a compound of theformula IV ##STR19## wherein R⁶, R⁷, R⁸ and R⁹ have the meanings definedabove and Q is Br, Cl or I; and reacting the compound with hydrazine toform a compound of the formula V ##STR20## wherein R⁶, R⁷, R⁸ and R⁹have the meanings defined above, and acylating the compound with anacylchloride with the general formula VI

    R.sup.1 --COCl                                             (VI)

wherein R¹ has the meaning as defined above for a compound of thegeneral formula I wherein X' and X" are C₁₋₆ -alkoxy to form a compoundof the formula VII ##STR21## wherein R¹, R⁶, R⁷, R⁸ and R⁹ have themeanings defined above, and hydrogenolysis of the compound to form acompound of the formula VIII ##STR22## wherein R¹, R⁶, R⁷, R⁸ and R⁹have the meanings defined above, and followed by thermal cyclization andsimultaneous deoxygenation to form a compound of formula I, wherein X'and X" independently are hydroxy or C₁₋₆ -alkoxy.